10-87961118-G-C
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000314.8(PTEN):c.1026G>C(p.Lys342Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
PTEN
NM_000314.8 missense, splice_region
NM_000314.8 missense, splice_region
Scores
6
10
3
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.43
Genes affected
PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.1026G>C | p.Lys342Asn | missense_variant, splice_region_variant | Exon 8 of 9 | ENST00000371953.8 | NP_000305.3 | |
PTEN | NM_001304717.5 | c.1545G>C | p.Lys515Asn | missense_variant, splice_region_variant | Exon 9 of 10 | NP_001291646.4 | ||
PTEN | NM_001304718.2 | c.435G>C | p.Lys145Asn | missense_variant, splice_region_variant | Exon 8 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
PTEN hamartoma tumor syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 04, 2024 | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 342 of the PTEN protein (p.Lys342Asn). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN hamartoma tumor syndrome (PHTS) (PMID: 23335809). ClinVar contains an entry for this variant (Variation ID: 92811). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 10866302, 29785012, 32350270). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 17, 2015 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2019 | The p.K342N variant (also known as c.1026G>C), located in coding exon 8 of the PTEN gene, results from a G to C substitution at nucleotide position 1026. This change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the lysine to asparagine at codon 342, an amino acid with similar properties. This variant has been reported in individuals with PTEN hamartoma tumor syndrome (PHTS); however, limited clinical details were provided (Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63). In addition, in vitro functional studies showed mixed results on phosphatase activity (Han SY et al. Cancer Res., 2000 Jun;60:3147-51). The nucleotide and amino acid positions are well conserved and highly conserved, respectively, in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct experimental evidence is unavailable. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Uncertain
Sift
Uncertain
D;.
Sift4G
Benign
T;D
Polyphen
D;.
Vest4
MutPred
Loss of methylation at K342 (P = 8e-04);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at